We have shown previously that the autonomous growth of the strictly interleukin-3 (IL-3)-dependent myeloid 32D cells requires the activation of two pathways minimally, a Myc- and a Raf-pathway. While enforced expression of Myc promotes cell cycle progression in the absence of IL-3, it is also deleterious to cell survival and accelerates apoptosis. Oncogenic Raf actively suppresses the onset of apoptosis and thus provides a survival factor to these cells. v-raf synergizes in apoptosis suppression with a weakly transforming oncogene, bcl-2, which has been shown earlier to suppress apoptosis in a variety of cell types. BCL-2 seems to function in a pathway parallel to Raf, since Raf-1 kinase did not affect the levels or the phosphorylation status of BCL-2 protein. The data obtained with Myc and Raf in the 32D cell system and data obtained in systems with the ability to differentiate showed that v-raf was compatible with or induced differentiation, whereas myc by itself was ineffective or blocked differentiation. These findings led us to postulate that the ratio of Raf- to Myc-pathway activity induced by a certain receptor will determine the outcome of the stimulation in terms of cell fate (proliferation, differentiation, or apoptosis). This model is supported by our findings in the PC12 cell system. (i) Analysis of isolated Myc- and Raf-pathways in PC12 cells showed that activated Raf efficiently induced differentiation, whereas Myc showed toxic effects. (ii) The differentiation factor "nerve growth factor" induced long-lasting activation of Raf-1 kinase, in contrast to the transient activation seen with epidermal growth factor. (iii) Finally, inhibition of c-myc by a dominant negative myc mutant converted the EGF into a differentiation factor.